Follistatin-like Protein-1 (FSTL-1), also known as FRP and TSC-36, is an extracellular glycoprotein belonging to the BM-40/SPARC/osteonectin family of proteins containing both extracellular calcium-binding and follistatin-like domains. See e.g., U.S. Pat. No. 6,410,232. FSTL-1 was originally cloned from an osteoblastic cell line as a TGF-β inducible gene. M. Shibanuma et al., Eur J Biochem 217, 13 (1993). The protein occurs in two isoforms resulting from differential sialylation. FSTL-1 has been detected in the medium of all osteosarcoma and chondrosarcoma cell lines, and in some cells of the fibroblast lineage. In mice, the highest expression of FSTL-1 has been observed in the lung. J. Mashimo et al., Cancer Lett 113, 213 (1997).
The action of FSTL-1 is unclear, and both proliferative and anti-proliferative effects have been reported. It is thought that FRP may play a role in neuralization during embryogenesis and its expression is upregulated by estrogen. See K. Okabayashi et al., Biochem Biophys Res Commun 254, 42 (Jan. 8, 1999) and T. Ohashi et al., Calcif Tissue Int 61, 400 (November 1997). In contrast to other BM-40 family members, the extracellular calcium-binding domain of FSTL-1 is non-functional, suggesting that, despite its sequence homology to BM-40, it has evolved clearly distinct properties. H. O. Hambrock et al., Journal of Biological Chemistry 279, 11727 (Mar. 19, 2004). Analysis of prostate cancers has revealed that over-expression of FSTL-1 may be associated with higher metastatic potential. L. Trojan et al., Anticancer Res 25, 183 (January-February, 2005). In contrast, FSTL-1 expression has been extinguished in v-ras-transformed rat fibroblasts, and transfection of FSTL-1 into these cells inhibited in vitro invasion and led to growth inhibition in human lung cancer cells. See I. M. Johnston et al., Oncogene 19, 5348 (Nov. 9, 2000) and K. Sumitomo et al., Cancer Lett 155, 37 (Jul. 3, 2000).
In 1998, Tanaka et al. cloned FSTL-1 from rheumatoid arthritis (RA) synovial tissue and demonstrated anti-FSTL-1 antibodies in the serum and synovial fluid of RA patients. M. Tanaka et al., International Immunology 10, 1305 (1998). In addition, it has previously been shown that FSTL-1 is highly-upregulated in the joints during the acute phase of collagen-induced arthritis (CIA), most prominently at the junction of synovium and eroding bone, suggesting a role in joint destruction. S. Thornton et al., Clin Immunol 105, 155 (2002). Furthermore, FSTL-1 expression in RA synovium has also been observed.
Tanaka et. al. recently reported that administration of human FSTL-1 to Balb/c mice with antibody-induced arthritis ameliorated disease, possibly by reducing synovial production of matrix metalloproteinases. See D. Kawabata et al., Arth Rheum 50, 660 (February, 2004) and M. Tanaka et al., International Immunology 15, 71 (January, 2003). The effect was mild and may be a consequence of using the human protein or using a mouse with a predominant Th2 phenotype (Balb/c). However, this finding has not been reproduced in the CIA model, and polymorphisms in FSTL-1 were not found to be associated with genetic susceptibility to RA. Y. Ehara et al., Clin Exp Rheumatol 22, 707 (November-December, 2004).
Based on the ability to bind various cell growth factors and extracellular matrices, follistatin modules have been proposed as regulators of growth factors and/or cytokines. See K. Sumitomo et al., Cancer Lett 155, 37 (Jul. 3, 2000).
All references cited herein are hereby incorporated by reference in their entirety.